3-158644602-C-T

Position:

• chr3-158644602-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024996.7(GFM1):​c.-33C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,544,880 control chromosomes in the GnomAD database, including 33,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2466 hom., cov: 33)
  • Exomes 𝑓: 0.21 (30748 hom.)
• Consequence: GFM1 NM_024996.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0250

Genes affected

GFM1 (HGNC:13780): (G elongation factor mitochondrial 1) Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-158644602-C-T is Benign according to our data. Variant chr3-158644602-C-T is described in ClinVar as [Benign]. Clinvar id is 343918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFM1	NM_024996.7	c.-33C>T		5_prime_UTR_variant	1/18	ENST00000486715.6	NP_079272.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFM1	ENST00000486715.6	c.-33C>T		5_prime_UTR_variant	1/18	1	NM_024996.7	ENSP00000419038	P1
GFM1	ENST00000264263.9	c.-33C>T		5_prime_UTR_variant	1/19	5		ENSP00000264263
GFM1	ENST00000478576.5	c.-33C>T		5_prime_UTR_variant	1/14	2		ENSP00000418755
GFM1	ENST00000478254.5	c.-33C>T		5_prime_UTR_variant, NMD_transcript_variant	1/18	5		ENSP00000417225

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26924 AN: 152176 Hom.: 2467 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.181 AC: 28092 AN: 155622 Hom.: 2725 AF XY: 0.183 AC XY: 15243 AN XY: 83452

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.104

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.207 AC: 288319 AN: 1392586 Hom.: 30748 Cov.: 28 AF XY: 0.206 AC XY: 141703 AN XY: 687362

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.0979

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.177 AC: 26938 AN: 152294 Hom.: 2466 Cov.: 33 AF XY: 0.174 AC XY: 12934 AN XY: 74456

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.189

Alfa AF: 0.189 Hom.: 599

Bravo AF: 0.176

Asia WGS AF: 0.124 AC: 431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.8
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28372852; hg19: chr3-158362391; COSMIC: COSV51835977; COSMIC: COSV51835977;